Contributors: Institut de Recherche en Infectiologie de Montpellier (IRIM); Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM); Université de Genève = University of Geneva (UNIGE); Ludwig Institute for Cancer Research; Montpellier Ressources Imagerie, Biocampus, CNRS, INSERM, Universite Montpellier, Montpellier, France; BioCampus (BCM); Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM); Université de Lausanne = University of Lausanne (UNIL); Immunologie des maladies virales, auto-immunes, hématologiques et bactériennes (IMVA-HB); Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay; Infectious Diseases Models for Innovative Therapies (IDMIT); Université Paris-Saclay-Institut de Biologie François JACOB (JACOB); Direction de Recherche Fondamentale (CEA) (DRF (CEA)); Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)); Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA); This work was supported by the Montage de Reseaux Scientifiques Européens ou Internationaux grant (N.J.A.) from the Agence Nationale de la Recherche , France; Sidaction grant for the salary of A.B., and by the Institut des sciences biologiques du Centre national de la recherche scientifique; The Swiss Cancer League (KFS-4404-02-2018)
Abstract: International audience ; Pathogens that persist in their host induce immune dysfunctions even in the absence of detectable replication. To better understand the phenotypic and functional changes that persistent infections induce in sentinel innate immune cells, we developed human PBMC-based HIV models of persistent infection. Autologous nonactivated PBMCs were cocultured with chronically infected, acutely infected, or uninfected cells and were then analyzed by unsupervised high-dimensional flow cytometry. Using this approach, we identified prevalent patterns of innate immune dysfunctions associated with persistent HIV infections that at least in part mirror immune dysfunctions observed in patients. In one or more models of chronic infection, bystander CD16$^+$ NK cells expressing markers of activation, such as CD94, CD45RO, CD62L, CD69, CD25, and immune checkpoints PD1, Tim3, TIGIT, NKG2A and Lag3, were significantly reduced. Conversely, helper ILC subsets expressing PDL1/PDL2 were significantly enriched in chronic infection compared with either uninfected or acute infection, suggesting that chronic HIV-1 infection was associated with an inhibitory environment for bystander ILC and NK subsets. The cell-based models of persistent infection that we describe here provide versatile tools to explore the molecular mechanisms of these immune dysfunctions and unveil the contribution of innate immunity in sustaining pathogen persistence
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